Clinical Trials Register

Summary
EudraCT Number:	2015-003179-32
Sponsor's Protocol Code Number:	ToL54304
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2015-003179-32

A.3

Full title of the trial

PREvention of Complications to Improve Outcome in elderly patients with acute Stroke. A randomised, open, phase III, clinical trial with blinded outcome assessment.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

PREvention of Complications to Improve Outcome in elderly patients with acute Stroke.

A.3.2

Name or abbreviated title of the trial where available

PRECIOUS

A.4.1

Sponsor's protocol code number

ToL54304

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN82217627

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Medical Center Utrecht
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 634809
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Utrecht
B.5.2	Functional name of contact point	Clinical trial coordinator
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 100
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031887571833
B.5.5	Fax number	0031302542100
B.5.6	E-mail	h.b.vanderworp@umcutrecht.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Paracetamol
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Paracetamol
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Rectal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Paracetamol
D.3.9.1	CAS number	103-90-2
D.3.9.2	Current sponsor code	AS3
D.3.9.3	Other descriptive name	PARACETAMOL
D.3.9.4	EV Substance Code	SUB09611MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ceftriaxone
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ceftriaxone
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CEFTRIAXONE
D.3.9.1	CAS number	73384-59-5
D.3.9.4	EV Substance Code	SUB07431MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Metoclopramide
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Metoclopramide
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use Rectal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METOCLOPRAMIDE
D.3.9.1	CAS number	364-62-5
D.3.9.4	EV Substance Code	SUB08902MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Stroke (ischaemic stroke or intracerebral hemorrhage)

E.1.1.1

Medical condition in easily understood language

Stroke (brain infarction or haemorrhage)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	PT
E.1.2	Classification code	10061256
E.1.2	Term	Ischaemic stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10022754
E.1.2	Term	Intracerebral hemorrhage
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	LLT
E.1.2	Classification code	10042244
E.1.2	Term	Stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess whether prevention of aspiration, infections and fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these, in the first four days after stroke onset improves functional outcomes at 90 days in elderly patients with acute stroke.

E.2.2

Secondary objectives of the trial

- To assess the effect of prevention of infections and fever in the first days after stroke onset with metoclopramide, ceftriaxone, paracetamol, or any combination of these, on the following outcomes at 90 days: death, death or dependency, quality of life, cognition, costs
- To detect specific populations classified by age, sex, stroke severity, body temperature, co-morbidities, and geographic region, in which the proposed treatments are particularly effective or not effective.
- To assess the effects of prophylactic treatment with ceftriaxone on antimicrobial resistance and the occurrence of infections with Clostridium difficile.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title: Detection of bacteria with 3rd generation cephalosporin resistance
Date: 06-2015 - 04-2020
Objective: To detect selection of bacteria with 3rd generation cephalosporin resistance caused by increased antibiotic pressure, a nested case-control substudy will be performed in 1000 patients in 30 centres in different participating countries. The presence of ESBL-producing bacteria will be assessed with PCR. With this purpose two rectal swabs will be collected in each patient, after specific informed consent, on admission and at day 7 (± 1 day, or at discharge, if earlier) and sent to the central laboratory at the AMC in Amsterdam, the Netherlands

E.3

Principal inclusion criteria

1. A clinical diagnosis of acute ischaemic stroke or intracerebral haemorrhage, confirmed with CT or MRI scan. A normal CT scan is considered compatible with ischaemic stroke;
2. A score on the National Institutes of Health Stroke Scale (NIHSS) ≥ 6, indicating moderately severe to severe stroke;
3. Age 66 years or older;
4. The possibility to start treatment within 24 hours of symptom onset;
5. Written informed consent.

E.4

Principal exclusion criteria

1. Active infection requiring antibiotic treatment, as judged by the treating physician;
2. Pre-stroke score on the mRS ≥4;
3. Death appearing imminent at the time of assessment.

In addition, patients will be excluded from participation in the trial treatment arms for any of the following reasons:
For the ceftriaxone arm:
1. Known hypersensitivity to beta-lactam antibiotics;
2. Clinical indication for antibiotic treatment; use of an antibiotic before screening is not an exclusion criterion.
For the paracetamol arm:
1. Known hypersensitivity to paracetamol or any of the excipients;
2. Known severe hepatic insufficiency;
3. Chronic alcoholism
4. Clinical indication for the use of paracetamol; incidental use of paracetamol before screening is not an exclusion criterion.
For the metoclopramide arm:
1. Hypersensitivity to the metoclopramide or to any of the excipients;
2. Gastrointestinal haemorrhage, mechanical obstruction or gastro-intestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk;
3. Confirmed or suspected pheochromocytoma;
4. History of neuroleptic or metoclopramide-induced tardive dyskinesia;
5. Epilepsy;
6. Parkinson's disease;
7. Use of levodopa or dopaminergic agonists;
8. Known history of methaemoglobinaemia with metoclopramide or of NADH cytochrome-b5 deficiency.
9. Clinical indication for the use of metoclopramide; incidental use of metoclopramide before screening is not an exclusion criterion.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure is the score on the modified Rankin Scale (mRS) at 90 days (± 14 days).

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary outcome will be evaluated on day 90 (± 14 days).

E.5.2

Secondary end point(s)

At 7 days (± 1 day) or at discharge, if earlier:
- Infections in the first 7 days (± 1 day; frequency, type, and C. difficile overgrowth syndrome). Infections will be categorised as diagnosed by the clinician, and as judged by an independent adjudication committee (masked to treatment allocation);
- 3rd generation cephalosporin resistance in the first 7 days (± 1 day), detected as part of routine clinical practice;
- Antimicrobial use during the first 7 days (± 1 day), converted to units of defined daily doses according to the classification of the WHO Anatomical Therapeutic Chemical Classification System with Defined Daily Doses Index;
- In a subgroup of patients: presence of Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria as detected by PCR in a rectal swab.

At 90 days (± 14 days):
- Death;
- Unfavourable functional outcome, defined as mRS 3 to 6;
- Disability assessed with the score on the Barthel Index (BI);
- Cognition assessed with the Montreal Cognitive Assessment (MoCA)
- Quality of life assessed with the EuroQol 5D-5L (EQ-5D-5L)
- Home time: duration of stay in the patient’s own home or a relative’s home over the first 90 days;
- Patient location over first 90 days (± 14 days): hospital; rehabilitation service; chronic nursing facility; home
- SAEs in the first 7 days.

E.5.2.1

Timepoint(s) of evaluation of this end point

As noted in E.5.2, the secondary outcomes will be on day 7(± 1 day) and day 90 (± 14 days).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Blinded outcome assessment

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

standard care as defined by local protocols and national and/or international guidelines

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

3800

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The large majority of patients with moderately severe to severe stroke have a diminished decision-making capacity because of a reduced level of consciousness, aphasia, or another cognitive disorder.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

460

F.4.2

For a multinational trial

F.4.2.1

In the EEA

3800

F.4.2.2

In the whole clinical trial

3800

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard care as defined by local protocols and national and/or international guidelines.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-11-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-09-06

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